Prostanoic acid intermediates

ABSTRACT

15- And/or 16-alkyl derivatives of 9,15-dioxygenated prost-13enoic, prosta-4,13-dienoic and prosta-5,13-dienoic acid, lower alkyl esters thereof and homologs thereof, as well as a process for preparing these derivatives are disclosed. The compounds possess hypotensive, anti-hypertensive, bronchospasmolytic, gastric acid secretion inhibiting, abortifacient, estrus synchronizing and ovulation regulating properties. The compounds also inhibit the aggregation of platelets and promote the disaggregation of aggregated platelets. Methods for their use are also disclosed.

United States Patent 1 [111 3,917,668

Abraham et al. Nov. 4, 1975 PROSTANOIC ACID INTERMEDIATES [75]Inventors: Nedumparambil A. Abraham,

Bollard des Ormeaux; Jehan Abraham, Tet. Letters, 451, 1973). Bagli,Kirkland; Tibor Bogri, Montreal, all of Canada [73] Assignee: AmericanHome Products Corporation, New York, NY.

[22] Filed: Apr. 16, 1973 [21] Appl. No.: 351,381

OTHER PUBLICATIONS McComie, Protective Groups in Organic Chemistry, pp.956 (1973).

Primary Examiner-Robert Gerstl [57] ABSTRACT [52] US. Cl... 260/468 D;260/240 R; 260/247.2 R; 15- And/or l6-alkyl derivatives of9,15-dioxygenated 260/268 R; 260/243,6 S; 260/3213; prost-l3-enoic,prosta-4,l3-dienoic and prosta-5,13- 260/340.4; 260/448 8 R; 260/468 11;dienoic acid, lower alkyl esters thereof and homologs 260/465 U; 260/468K; 260/48 5 R; thereof, as well as a process for preparing these deriv-260/50l 1; 260/504 5; 260/5()1 17; atives are disclosed. The compoundspossess hypoten- 260/50l.2; 260/514 D; 424/305; 424/317 sive,anti-hypertensive, bronchospasmolytic, gastric [51] Int. Cl. C07C6l//38; C07C 69/74 acid secretion inhibiting, abortifacient, estrussynchro- [58] Field of Search. 260/468 D, 448,8 R, 514 D, nizing andovulation regulating properties. The com- 260/410,9, 413, 345,7 345 8pounds also inhibit the aggregation of platelets and promote thedisaggregation of aggregated platelets. [56] References Cited I Methodsfor their use are also disclosed.

UNITED STATES PATENTS 9 Claims, No Drawings, 3,736,319 5/1973 Martel260/240 R 1 PROSTANOIC ACID INTERMEDIATES BACKGROUND OF THE INVENTIONThe chemistry and pharmacological effects of the prostaglandins havebeen the subject of several recent reviews; for example, see E. W.Horton, Physiol. Rev,

49, 122 (1969), J. F. Bagli in Annual Reports in Medicinal Chemistry,1969", C. K. Cain, Ed., Academic Press, New York and London, 1970, p.170, and J. E. Pike in Progress in the Chemistry of Organic NaturalProducts", Vol. 28, W. Herz, et al. Eds., Springer Verlag, New York,1970, p. 313. i f

The pharmacological effects known to be associated with theprostaglandins relate to the reproductive, cardiovascular, respiratory,gastrointestinal and renal systems.

Due to the increasing interest in these natural.products a ratherextensive effort hasbeen given recently to the synthesis ofprostaglandins and their analogs. lncluded among these syntheses areseveral synthetic methods for the preparation of,9,,il'5-dioxyge natedderivatives of. prostanoic or prostl13-enoic acid.For example, thesynthesis of the first pharmacologically active 9,15-dioxygenatedprostanoic acid derivative, 96,1SE-dihydroxyprost-l 3 enoic ,acid, l1-desoxypros-, taglandin F was reported in detail by J. F.'Bagli, T.Bogri and R. Deghengi, Tetrahedron Letters, 465

2 Amer. Chem. Soc. 94, 7823 (1972), A. F. Kluge, et al., J. Amer. Chem.Soc., 94, 9256 (1972), and N. A. Abraham, Tetrahedron Letters, 451,1973.

More recently, Bagli and lBogri have extended the scope of theirprocesses for preparing 9,15-dioxgenated derivatives of prostanoic acidto include the preparation of 9-oxo-l5-hydroxy prostanoic acidderivatives having analkyl substituent at position 15, U.S. Pat. No.3,671,570, issued June 20,, 1972. These 15- alkyl derivatives possesshypotensive, antihypertensive, bronchospasmolyticand gastric acidsecretion inhibiting properties, as well as inhibiting the aggregationof platelets and promoting the disaggregation of aggregated platelets.

lt is noteworthy that the synthetic 9,15-dioxygenated prostanoic acidderivatives described above possess a" number of the biologicalactivities of the natural compounds although they lack the ll-hydroxylof the latter. 2O

In the natural series attention hasbeen focused recently on certainIS-methyland 16,16-dimethyl derivatives.

-l5 -Methyl PGF and lS-methyl PGE methyl esters have been reported tointerrupt pregnancy in the rhesus monkey and in the human. K. T. Kirtonet al., Ann. N.Y. Acad. Sci., 180, 445(1971). Furthermore,

i5(R)-methyl and l5(S)-methyl PGE has been reported to inhibit gastricsecretion, see Medical World News, Oct. 20, 1972, p. 70M. Likewise,16,16-dimethyl PGE methyl ester has been described as effective ininhibiting gastric acid secretion, Chemistry, ad Engineering News, Oct.16, 1972., p. 12.

It is worth noting at this point that the natural PGE,,- PGE PGF and PGFdo have the disadvantage of being relatively unstable, see T. O.Oesterling, et al., J. Pharm. Sci., 61, 1861 (1972). For example, it iswell known that the ll-hydroxy group of PGE and PGE participates readilyin dehydration reactions under both basic and acidic conditions, see S.Bergstrom et al., Biol. Chem. 238, 3555 (1963'), E. J. Corey et al., J.

Amer. Chem. Soc, 90, 3245 (1968), J. E. Pike et al., J. Org. Chem. 3552(1969) and 4Prostaglandins,

Progress in Research--, SfMJ-M. Karim, Ed., Wileylhterscience, New York,1972, p. 10. 1

As realized by those skilled in the art this inherent disadvantageof thenatural-compounds must always be I taken into account when consideringthe practical as- (1966). A significant simplificationand modificationpf5 that process was described by Bagli and Bog ri in US. Pat. No.3,455,992, issued July 15,1969, whereby logs thereof wereobtained, seealso Bagli and Bogri, Tetrahedron Letters, 5 (1967). V

Further improvements in the synthesis of 9,15-dioxygenated derivativesof prostanoic acid have been described by -Bagli and Bogri inTetrahedron Letters, 1639 (1969) and German"O'ffenlegungsschrift No.

95,15fi-dihydroxyprost-l3-enoic acid as well as homopects ofpreparation,formulation of storage of these compounds. In contrast, thecompounds of the present invention are freefrom thisdisadvantage.

derivatives of natural prostaglandins have been described as exhibitingeffects on the gastrointestinal system, and although certain methylesters of the 15- 1,953,232, published Apr. 30,1970, and in BritishvPat.

Specification No. 1,097,533, published Jan. 3, 1968.

Other recentsynthesis of. 9,15-dioxygenated derivatives are reported inBelgian Pat. No. 766,521, published Nov. -3, 1971, P. Crabbe and A.Guzman, Tetra-, hedron Letters, (1972), M.-P. L. Caton, etal.,Tetrahedron Letters, 773 (1972), C. J. Sih, et al.,TetrahedronLetters, 2435 (1972), F. S. Alverez, et al., J.

alkylated natural derivatives have been described as having effects onthe reproductive system, it would appear that the latter effects havenever been associated .with 15- and/or 16-alkyl analogs of the9,15-dioxygenated derivatives. I

lt is the purpose of the present application to disclose the discoveryof certain stable l5-alkylated and/or 16- alkylated derivatives of the9,15-dioxygenated derivatives of prostanoic acid having unexpected highactivity tive agents for inducing abortion and for synchroniza- 3 ,91 7,668 3 4 tion of estrus and regulation of ovulation in animals. areagent known to be effective for converting a hydroxy group of knowncompounds to a protected hy- SUMMARY OF THE INVENTION droxy group, toobtain the corresponding compound of The compounds prepared by theprocess of this informula 4 in which L is the said radical A, R R Rvention are represented by formula 1: 5 and n are as defined herein andR is a radical suitable for protecting a hydroxy group.

Y Thereafter, the instant compound of formula 4 is CH Z (CH )COoRltreated with a malonic ester derivative of formula 5 Q 2 2 m l in whichR and R each are lower alkyl and Z and m are as defined herein, inthepresence of a base whereby the compounds of formulae 4 and 5 undergoa base catalyzed condensation to give the correspondingcyclopentanonetriester of formula 6,

in which m is an integer from O to 2, nis an integer from 2 to 5, X andY together represent oxo, or X represents hydroxy and Y is hydrogen, Zrepresents the radical (CH cis-CH=CHCH or cis-CH CH=)\ CH, R is hydrogenor lower alkyl and R, R and R each are hydrogen or lower alkyl with theprovisos that at least one of R R or R is lower alkyl and at least 0COORB one of R, R or R is hydrogen. cn,-z cll,),,coolvfl,

Among the preferred compounds of this invention Rsooc are the compoundsof formula 1 in which m is the integer 2 and n is the integer 3. aCH=CH-CCRR(CH,),,CH, 6

The compounds of formula lare prepared by a prosuitable'for protecting ahydroxy group and Z and m cess in which the starting material is thealdehyde of for lL-CHO 2' h'hLth d' lA,B c;

mu a m w c S e m ca or which s Z, R2, R, R", R5 and R are as defined A Bc h R dR h l lkl,R' d' l I w erem an eac are ower a y a m herelnbefore,R ISJOWCI alkyl and R ls hydrogen or a I radical suitable for protectinga hydroxy group; folv lowed, when R" is a radical suitable forprotecting a hydroxy group, by treating the last-named cyclopentanonetriester of formula '6 with an agent known to be In the case whereL of the aldehyde of formula c v f li g- P' fi ql L-CHO is radical A,the aldehyde is treated with a cd'respdnding 6 which hydrogen.

Wlttl rea ent of the formula (AlkO) POCH coca a y R( CH:,,CH in whichAlk is an alkyi contai hing one compound f formula 6 9 treated to threecarbon atoms and R3, R4'and n are as defined wlth a base ln the presenceof water to glve the corret th d f sponding keto compound of formula 1which m,'n,' Z, is gfig g g o obtam e correspo'n g compoun 0 R R and R,are as defined herein, X and Y together (3) are oxo and R is hydrogen:thereafter, and if desired,

the last-named compound is treated with a lower alkain whi h L, R", Rand n ar a d fined herei b fo nol containing one to three carbon atomsin the presare as defined hereinbefore.

Depending onthe nature of L of the aldehyde of formula L-CHO, theprocess of this invention is elabo- 45 rated in the following manner: 1

the last-named compound of formula 3 is then treated ence Of an acicatalyst to obtain the corresponding with a metal borohydride or a loweralkyl magnesium ester derivative of formula i in which m, n, Z, R Rhalide to give the corresponding compound of formula and R a e asdefined herein, X and Y togetherare oxo 4 v and R is lower alkyl.

Alternatively, in the case where L of the aldehyde of (4) formula L-CHOis radical B, the aldehyde is-treated with the above Wittig reagent offormula (AlkO containing 1 to 3 carbon atoms and R", R and n are as inwhich L is the radical A as defined herein, R, R and definedhereinbefore, to obtain the corresponding n are as defined herein, R ishydrogen and R is respeccompound of formula 3,-noted above, in which Lis, the

tively hydrogen or lower alkyl; optionally followed by radical B asdefined hereinbefore'and R, R and n are treating the compound of formula4, so obtainedpwith as defined hereinbefore.

Thereafter the compound of formula 3 is treated with either a metalborohydride or a lower alkyl magnesium halide to give the correspondingcompound of formula 4, as noted above, in which L is the radical B asdefined herein, R R and n are as defined herein, R is hydrogen and R isrespectively hydrogen or lower alkyl, followed by subjecting the lattercompound to conditions known to be effective for removingthe radicalsuitable for protecting a hydroxy group of known compounds, to give thecorresponding compound of formula 1 in which m, n, Z, R, R and R are asdefined herein, X is hydroxy, Y is hydrogen and R is lower alkyl.

Thereafter, and if desired, the last-named compound of formula 1 inwhich R is lower alkyl is treated with an oxidizing agent to afford thecorresponding keto com pound of formula 1 in which m, n, Z, R and R areas defined hereinbefore, R and R are lower alkyl and X and Y togetherare oxo.

Again alternatively, in the case where L of the aldehyde of formula LCHOis radical C, the aldehyde is treated with a Wittig reagent of theformula (Alk0) POCH COCR R (CI-I ),,CI-I in which Alk is an alkylcontaining 1 to 3 carbon atoms, R and R each are'hydrogen or lower alkylwith the proviso that at least one of R or R is lower alkyl and n is asdefined hereinbefore, to obtain the corresponding compound of formula 3noted above, in which L is the radical C as defined hereinbefore and R,R and n are as defined hereinbefore.

Thereafter, the instant keto compound of formula 3 is converted to acorresponding ketal derivative, viz., the compound of formula 3 in whichL is the radical D:

in which Z and m are as defined hereinbefore and R is lower alkyl, bytreating said keto compound with ethylene glycol in the presence of anacid catalyst.

The ketal derivative of formula 3 is now treated with a metalborohydride to give the corresponding compound of formula 4, notedabove, in which L is the said radical D, R, R and n are as definedherein, R is hydrogen and R is hydrogen; followed by treating saidlast-named compound with an acid in the presence of water to obtain thecorresponding compound of formula l.

Thereafter, if desired, the aforementioned ester compound of formula 1in which R is lower alkyl, obtained by any of elaborations of theprocess noted above, is

converted to its corresponding free acid, a compound,

of formula 1 in which R is hydrogen, by treatment with a base in thepresence of water.

Likewise, if desired, the aforementioned keto compound of formula 1 inwhich X and Y together are oxo, obtained by any of the elaborations ofthe process noted above, is treated with a complex borohydride to givethe corresponding compound of formula 1 in which X is hydroxy and Y ishydrogen.

6 DETAILS OF THE INVENTION The numbering system applied to the compoundsof this invention, as used hereinafter, refers to the(ucyclopentyl(lower)alkanoic acid nucleus.

A feature of this invention is that the process described herein leadsto the compounds of formula 1 in which the two side chains are in thetrans configuration characteristic for the natural prostaglandins. Also,like the natural prostaglandins a double bond in the acid side chain ofthe compounds of this invention has the cis configuration and the doublebond in the side chain bearing the hydroxy group has the transconfiguration.

Notwithstanding the preceding considerations the compounds of thisinvention having one or more asymmetric carbon atoms can exist in theform of various stereochemical isomers. More specifically, the compoundsare produced as a mixture of racemates. These mixtures result from theasymmetric centers bearing a hydroxyl group and can be separated intopure racemates at appropriate stages by methods well known in the art,for example, see below. If desired, the racemates can be resolved intoenantiomorphs also by known methods. It is to be understood that suchracemates and enantiomorphs are included within the scope of thisinvention.

Furthermore, it is to be understood that the pictorial representationsused herein illustrating the compounds of this invention, are to beconstrued as including such racemates and enantiomorphs. For example, informula 1 the dotted line joining the acid side chain to thecyclopentane ring and the solid line joining the side chain bearing thehydroxy group are used for the purpose of illustrating the transrelationship of these two side chains and should not be construed aslimiting the compounds to one enantiomorph but rather as including allpossible enantiomorphs having this trans relationship.

Also included within this invention are the pharmaceutically acceptablesalts of the acids of formula 1 in which R is hydrogen. The lattercompounds are transformed in excellent yield into the correspondingpharmaceutically acceptable salts by neutralization of said lattercompoundswith the appropriate inorganic or organic base. The relativestability of the acid facilitates this transformation. The salts possessthe same activities as the parent acid compounds when administered toanimals and may be utilized in the same manner. Suitable inorganic basesto form these salts include, for example, the hydroxides, carbonates,bicarbonates or alkoxides of the alkali metals or alkaline earth metals,for example, sodium, potassium, magnesium, calcium and the like.Suitable organic bases include the following amines: lower mono-, diandtrialkylamines, the alkyl radicals of which contain up to 3 carbonatoms, such as methylamine, dimethylamine, trimethylamine, ethylamine,diand triethylamine, methylethylamine, and the like; mono-, diandtrialkanolamines, the alkanol radicals of which contain up to 3 carbonatoms, such as mono-, diand triethanolamine; alkylene-diamines whichcontain up to 6 carbon atoms, such as hexamethylenediamine; cyclicsaturated or unsaturated bases containing up to 6 carbon atoms, such aspyrrolidine, piperidine, morpholine, piperazine and their N- alkyl andN-hydroxyalkyl derivatives, such as N-methyl-morpholine andN-(2-hydroxyethyl)-piperidine, as well as pyridine. Furthermore, theremay be mentioned the corresponding quaternary salts, such as thetetraalkyl (for example tetramethyl), alkyl-alkanol (for examplemethyl-triethanol and trimethyl-monoethanol) and cyclic ammonium salts,for example the N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)-pyrrolidinium, N,N-dimethylmorpholinium,N-methyl-N- (2-hydroxyethyl)morpholinium, N,N-dimethylpiperidinium andN-methyl-N-(2-hydroxyethyl)- piperidinium salts, which are characterizedby an especially good water-solubility. In principle, however, there canbe used all ammonium salts which are physiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the selected acid in water containingat least an equivalent amount of a hydroxide, carbonate, or bicarbonatecorresponding to the inorganic salt desired. Advantageously, thereaction is performed in an inert organic solvent, for example,methanol, ethanol, dioxane, and the like. For example, such use ofsodium hydroxide, sodium carbonate or sodium bicarbonate gives asolution of the sodium salt. Evaporation of the water or addition of awater-miscible solvent of moderate polarity, for example, a loweralkanol or a lower alkanone gives the solid inorganic salt if that formis desired.

To produce an amine salt, the selected acid is dissolved in a suitablesolvent of either moderate or lower polarity, for example, ethanol,acetone, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthen added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of low polarity, for example, benzene or diethyl ether or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use equivalent amounts ofthe less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe selected acid with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

The term lower alkyl as used herein contemplates straight chain alkylgroups containing from one to three carbon atoms and includes methyl,ethyl and propyl.

The term complex borohydride as used herein contemplates the metalborohydrides, including sodium borohydride, potassium borohydride,lithium borohydride, zinc borohydride and the like, and metaltrihydrocarbylborohydrides including lithium 9-alkyl-9-borabicyclo[3,'3,l]nonylhydride, in which the alkyl contains one toseven carbon atoms, preferably lithium 9-tert-butyl-9-borabicyclo[ 3,3,l ]nonylhydride, prepared according to the procedure described inGerman ment of conditions associated with high blood pressure, in thetreatment of asthmatic conditions, in the treatment of pathologicalconditions associated with excessive secretion of gastric acid such as,for example, peptic ulcer, in population control, and in animalhusbandry. In addition, the compound of this invention inhibit theaggregation of platelets and promote the disaggregation of aggregatedplatelets, and are useful as agents for the prevention and treatment ofthrombosis.

More particularly, these compounds, when tested in a modification of thetests for determining hypotensive activities described in ScreeningMethods in Pharmacology, Academic Press, New York and London 1965, page146, using the cat in urethane-chloralose anaesthesia as the test animaland measuring mean arterial blood pressure before and after intravenousadministration of the compounds, have exhibited utility as hypotensiveagents. When tested in the renal hypertensive rat, prepared by themethod of A. Grollman described in Proc. Soc. Exp. Biol. Med., 7, 102(1954), and measuring blood pressure by the method described by H.Kersten, J. Lab. Clin. Med., 32, 1090 (1947), they have exhibitedutility as antihypertensive agents.

Moreover, the compounds of this invention, when tested in a modificationof the test method described by A. K. Armitage, et al., Brit. J.Pharmacol, 16, 59 (1961), have been found to alleviate bronchospasms,and are useful as bronchospasmolytic agents.

Furthermore, the compounds of this invention, when administered to ratsin the test method described by H. Shay, et al., Gastroenterol., 26, 906(1954), have been found to inhibit the secretion of gastric acid, andare useful as agents inhibiting the secretion of gastric acid.

In addition, the compounds of this invention, when tested in amodification of the test method described by G. V. R. Born, Nature, I94,927 (1962), using the aggregometer manufactured by Bryston ManufacturingLimited, Rexdale, Ontario, Canada, have been shown to inhibit theaggregation of platelets and to promote the disaggregation of aggregatedplatelets, and are use ful as agents for the prevention and treatment ofthrombosis.

When the compounds of this invention are employed as hypotensive oranti-hypertensive agents, as agents inhibiting gastric acid secretion inwarm-blooded animals, for example, in cats or rats, as agents for theprevention or treatment of thrombosis, or as bronchospasmolytic agents,alone or in combination with pharmacologically acceptable carriers,their proportions are determined by their solubilities, by the chosenroute of administration, and by standard biological practice. Thecompounds of this invention may be administered orally in solid formcontaining such excipients as starch, lactose, sucrose, certain types ofclay, and flavouring and coating agents. However, they are preferablyadministered parenterally in the form of sterile solutions thereof whichmay also contain other solutes, for example, sufficient sodium chlorideor glucose to make the solution isotonic. For use as bronchospasmolyticagents, the compounds of this invention are preferably administered asaerosols.

The dosage of the present hypotensive, antihypertensive, gastric acidsecretion inhibiting, or bronchospasmolytic agents, or agents for theprevention and treatment of thrombosis will vary with the forms ofadministration and the particular hosts under treatment. Generally,treatments are initiated with small dosages substantially less than theoptimum doses of the com- 9 pounds. Thereafter, the dosages areincreased by small increments until the optimum effects under thecircumstances are reached. In general, the compounds of this inventionare most desirably administered at a concentration level that willgenerally afford effective results without causing any harmful ordeleterious side effects and preferably at a level that is in a range offrom about 0.1 mg to about 10.0 mg per kilo, although as aforementionedvariations will occur. However, a dosage level that is in the range offrom about 0.5 mg to about mg per kilo is most desirably employed inorder to achieve effective results. When administering the compounds ofthis invention as aerosols the liquid to be nebulized, for example,water, ethyl alcohol, dichlorotetrafluoroethane anddichlorodifluoromethane, contain preferably from 0.005 0.05 per cent ofthe acid, or a non-toxic alkali metal, ammonium or amine salt thereof,or ester of formula 1.

Furthermore, when the compounds of this invention are tested by themethod of A. P. Labhsetwar, Nature, 230, 528 (1971) whereby the compoundis given subcutaneously on a daily basis to mated hamsters on days 4, 5and 6 of pregnancy, thereafter the animals being sacrificed on day 7 ofpregnancy and the number of abortions counted, the compounds are shownto have abortifacient properties.

For example, complete abortion resulted in all animals when thefollowing compounds of formula 1 were tested according to this method atdoses noted below:

trans, cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid (Example 59), 2.5 mg/kg/day,

trans, cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-4-heptenoic acid (Example 59) 2.5 mg/kg/day, and

trans, cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoic acid (Example 75), 0.5 mg/kg/day.

The potency of the above unsaturated compounds is especially noteworthyin light of the fact that the completely saturated l5-methyl analog,2-(3-hydroxy-3- methyloctyl)-5-oxocyclopentaneheptanoic acid, describedin US. Pat. No. 3,671,570, cited above, does not cause complete abortionin the above test at doses less than 30 mg/kg/day.

Furthermore, the compounds of this invention are useful for inducinglabor in pregnant animals at or near term. When the compounds of thisinvention are employed as agents for abortion or for inducing labor, thecompounds are infused intravenously at a dose 0.01 to 100 mg/kg perminute until the desired effect is obtained.

Still furthermore, the compounds of formula 1 are useful for thesynchronization of estrus and the regulation of ovulation in animals.

It is often desirable to synchronize estrus in domestic animals, forexample, horses, cattle, sheep, swin'e or dogs, in order to be able toperform artificial insemination or mating with a male of the desiredgenetic quality under optimum conditions. In the past, this has beendone by administering to the animals an ovulationinhibiting agent,withdrawing administration of said agent shortly before the date chosenfor mating or artificial insemination, and relying either upon thenatural production of LH and FSH to induce ovulation and to produceestrus or by administering gonadotrophins. However, this procedure wasnot entirely satisfactory because ovulation at a predetermined timeoccured only in a certain proportion of the animals when gonadotrophinswere not used. On the other hand, the high cost of gonadotrophins andside effects encountered in their administration made this methodimpractical. It is now possible to obtain substantially completesynchronization of ovulation and of estrus, by treating the animals in agiven group with the compound of formula 1 before the predeterminedperiod of time for mating or artificial insemination, so as to obtainovulation and estrus within that time interval. The delay in the onsetof ovulation and estrus following administration of the compound of thisinvention varies with the species of animal. For example, in rodentssuch as rats or hamsters ovulation takes place within 18 hours followingadministration of the compound and in the horse ovulation usually takesplace within one week after the compound is given.

More specifically, synchronization of estrus and regulation of ovulationin the horse is achieved by giving the compound of formula 1, eitherrandomly to a group of horses during the life of the corpus luteum(usually day 5 to day 16 of the cycle) or 2 to 3 days prior to theexpected onset of estrus. The compound for example, trans,cis-7-[2a-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoic acid, is given by intrauterineinfusion, subcutaneously or intramuscularly in sterile solutions. Adosage which is in the range of from about 1 to 100 mg/lOOO lb,preferably 5 to 25 mg/lOOO lb is employed and is administered as asingle dose or spread over a period of 72 hours. Practically speaking itis preferable to give one-half the total dose on 2 consecutive days forthe latter form of administration. For example, in a group of horsesreceiving this medication on the second and third day before expectedestrus, estrus follow-s within 24 to 48 hours which in turn is followedby ovulation occuring in the majority of animals, from the fourth to thesixth day thereafter as determined by rectal palpation of the ovaries.

In'a control group receiving no medication the occurance of ovulationwas spread rather unevenly over the third to eighth day after the onsetof estrus.

The process of this invention may be illustrated as shown in theaccompanying flow sheet.

With reference to the starting materials required for the above process,the aldehyde of formula LCHO in which L is radical A wherein R is ethylhas been described by D. T. Warner, J. Org. Chem., 24, 1536 (1959). Byfollowing the process described therein for the preparation of thataldehyde and using the appropriate di(lower)alkylbromomalonate thealdehydes of formula L-CHO in which L is radical A wherein R is a loweralkyl other than ethyl are obtained.

The aldehyde of formula L-CHO in which L is the radical B or C isprepared according to the procedure described in the copending US.application Ser. No. 259,896, filed June 5, 1972. Briefly, thesestarting materials are prepared in the following manner (the symbols mand Z in the following description have the same significance asdescribed hereinbefore): A lower alkyl ester of 2-(wcarboxy(CH -ZCH)cyclopent- 2-en-1-one, preferably the methyl ester, convenientlyprepared by treating a 2-(w-carboxy(CH ),,,ZCH )cyclopent-2-en-l-one(7), see below, with a lower alkanol containing from l-6 carbon atoms,preferably methanol, and p-toluenesulfonic acid, is treated withnitromethane in the presence of an alkali metal lower alkoxide,preferably sodium ifietl'ioxide, to

yield the corresponding lower alkyl ester, preferably the methyl ester,of a 2-(m-carboxy-(CH ),,,ZCH )--3-nitromethylcyclopentan-l-one. Thel-keto group of the latter is reduced with sodium borohydride to yieldthe corresponding lower alkyl ester of 2(mcarboxy(CH ),,,ZCH)3-nitromethylcyclopentan-l-ol, preferably the methyl ester.

The latter two compounds, the 3-nitromethylcyclopentan-l-one and the3-nitromethylcyclopentan-l-ol derivatives are converted to theirrespective aci-forms by treatment with a strong base such as an alkalimetal lower alkoxide, preferably sodium methoxide, or an aqueous alkalimetal hydroxide, preferably sodium hydroxide, and the resulting solutionof the alkali metal salt of the corresponding nitronic acid is added toa cold aqueous solution of a mineral acid, preferably dilute sulfuricacid at a temperature in the range between about -lC and about 25C,preferably in the vicinity of 0C. Extraction of the mixture with awater-immiscible solvent, preferably diethyl ether, and evaporation ofthe latter yields respectively the corresponding 3- aldehyde, namely thedesired ketoaldehyde starting material of formula L-CHO in which L isthe radical C and the unprotected hydroxyaldehyde, precursor to thedesired starting material of formula L-CHO in which L is the radical B.The latter precursor is thereaf ter transformed into the desiredstarting material of formula L-CHO in which L is the radical B wherein Ris a radical suitable for protecting a hydroxy group, for example,tetrahydropyran-2-yl (THP), trimethylsilyl (TMS), dimethylisopropylsilyl(DMlS) and tert-butyl, Said transformation is effected by treating theprecursor with a reagent known to be effective for converting a hydroxygroup of a known compound to a protected hydroxy group. Such reagentsinclude an excess of dihydropyran and an acid catalyst for example,p-toluenesulfonic acid, hydrogen chloride or sulfuric acid, for the THPgroup, trimethylchlorosilane with hexamethyldisilazane for the TMSgroup, dimethylisopropylchlorosilane anddiisopropyltetramethyldisilazane for the DMlS group or isobutylene forthe tertbutyl group. t

The lower alkyl ester of 2(w-- carboxy,--(CH ),,,ZCH)cyclopent-2-en-l-one (7), noted above, is

prepared by the following convenient process:

+Br-CH,-z--(CH,),,,C00R

in which 2 and m area as defined in the first instance and R is loweralkyl.

With reference to the first step of this process [,3- cyclohexadione (8)is condensed with an appropriate lower alkyl w-bromoester of formula 9in the presence of an alkali metal alkoxide in a lower alkanol,preferably sodium methoxide in methanol, to give the dione of formula10.

The latter compound is then treated with t-butyl hypochlorite in themanner described by G. Buchi and B. Egger, J. Org. Chem., 36, 2021(1971), to yield the chloro derivative ll. The latter treatment isperformed preferably under a nitrogen atmosphere using dry chloroform asa solvent. Thereafter, the chloro derivative is treated in a hydrocarbonsolvent, preferably toluene, in the presence of an alkali metalcarbonate, preferably sodium carbonate, at temperatures from to C fromabout 5 to 25 hours whereby ring contraction is effected to yield thedesired lower alkyl ester of 2-(wcarboxy(CH -Z-CH )cyclopent-2-en-l :one(7).

The w-bromoacids and the lower alkyl w-bromoesters of formula 9 utilizedfor the preparation of compound 7 are either known, for example,7-bromo-5-heptenoic acid its corresponding ethyl ester and severalhomologs of these compounds are described in Belgian Pat. No. 766,520,published Nov. 3, 1971, or may be prepared by standard methods; forexample, see Rodds Chemistry of the Carbon Compounds, S. Coffey, Ed.,Vol. lc, 2nd Ed., pp. 201 252 and the copending application, Ser. No.238,650, filed Mar. 27, 1972.

In practising the process of this invention, the aldehyde of formula I.CHO in which L is the radical A, B or C is used as the startingmaterial. This aldehyde is treated with a Wittig reagent of the formula(AlkO POCH COCR R (CH ),,CH in which Alk is an alkyl containing one tothree carbon atoms and R, R and n are as defined hereinbefore, in thepresence of an alkali metal hydride, preferably sodium hydride, and inan aprotic solvent, preferably dimethoxyethane or dimethyl formamide.Acidification with an aqueous acid, preferably aqueous acetic acid,extraction with a waterimmiscible solvent, preferably diethyl ether,followed by washing, dryring and evaporation of the latter, yields thecorresponding compound of formula LCH=CH- COCR R-(CH,),,CH;,.

The requisite Wittig reagents are prepared by the method of E. J. Coreyand G. T. Kwiatkowski, J. Amer Chem. Soc., 88, 5654 (1966) using theappropriate: lower alkyl alkanoate and di(lower)alkyl oi-lithiorne- 13thanephosphonate.

More specifically, the treatment of the aldehyde derivative of formulaLCHO in which L is the radical A, B or C with the ylid prepared from theWittig reagent is performed in the following manner. A solution of theWittig reagent in about to parts of an aprotic solvent, preferablydimethoxyethane or dimethylformamide, is added slowly under a blanket ofnitrogen to a stirred suspension of approximately one equivalent of analkali metal hydride, preferably sodium hydride, in approximately 150parts of the aprotic solvent and stirring is continued at roomtemperature for a period of time of from 10 to 60 minutes, preferablyfor about 30 minutes. To the resulting solution of the correspondingyield, there is slowly added a solution of approximately to 1equivalent, preferably about 0.85 equivalent, of the aldehyde of formulaLCHO in about 5 to 10 parts, preferably about 8 parts of an aproticsolvent, preferably dimethoxyethane. The addition is carried out at to100C, preferably to 65C over a period of time of from 5 to 60 minutes.Acidification with an aqueous acid, preferably aqueous acetic acid,followed by extraction with a water-immiscible solvent, preferablydiethyl ether, washing and drying of the extracts, evaporation of thesolvent, and chromatography of the residue on silica gel yields thecorresponding compound of formula LCH CHCOCR R "-(CH ),,CH (3) in whichL is the radical A, B or C and R, R and n are as defined hereinbefore.

Before proceeding further with the process of this invention it isexpedient, in the case where L of the lastnamed compound of formula 3represents the radical C, to protect the l-keto group of thecyclopentanone ring of radical C. Said protection is advantageouslyafforded by treatment of the compound of formula 3 in which L is radicalC with ethylene glycol in the presence of an acid catalyst, for example,p-toluenesulfonic acid, hydrogen chloride or sulfuric acid, in an inertsolvent, for example, benzene or tetrahydrofuran. In this manner thecorresponding compound of formula 3 is obtained in which L is theorganic radical D, as defined hereinbefore, having said protected ketogroup.

Also it is worth noting at this point that a convenient alternativemethod has been found for the preparation of the compound of formula 3in which L is the radical A as defined herein and R, R and n are asdefined in the first instance. In this latter method, the aldehyde offormula LC1-IO in which L is the radical A is treated with a methylketone of formula C1-I COR in which R is CR R(Cl-I ),,CI-I in which R Rand n are as defined in the first instance, in the presence of a base,to

which in this case is the desired compound of formula 3 in which L isthe radical A and R", R and n are as defined in the first instance.

The aforementioned treatment of the aldehyde with the ketone of formulaCI'I COR is performed preferably by using an organic base, for example,piperidine, Nmethylpiperidine or N,N-dimethylpiperazine, although sodiumhydride, potassium tert-butoxide, sodium ethoxide and the like arealternative suitable bases. If desired an inert solvent, for example,benzene, ether, dioxane or tert-butanol, is employed for this reaction.Although not critical, it is prudent to use substantially equivalentamounts of the aldehyde and the ketone for the reaction. Advantageoustemperatures 14 and times for this reaction include a temperature rangeof from 20 to 100C, preferably 60 to C, and a reaction time from two to30 hours.

The instant compound of formula 3 in which L is the radical A, B or D isnow converted to the corresponding compound of formula 4 by one of thefollowing two methods depending on R of the product being hydrogen orlower alkyl.

When it is desired to obtain the compound of formula 4 in which L is theradical A, B or D and R is hydrogen, then the compound of formula 3 inwhich L is the radical A, B or D is treated with a metal borohydride,for example, lithium borohydride, potassium borohydride, zincborohydride or preferably sodium borohydride, in an inert solvent, forexample, methanol or tetrahydrofuran, to yield the desired compound offormula 4 as a mixture of epimers. The epimers result from theasymmetric center at the carbon to which the secondary alcohol isattached. The mixture of epimers need not be separated at this stage. Inpractice it has been found more convenient to continue the process withthe mixture of epimers and, if desired, to separate the resultingepimers of compounds of formula 1.

When it is desired to obtain the compound of formula 4 in which L is theradical A or B and R is lower alkyl then the latter compound of formula3 in which L is the radical A or B is treated with a lower alkylmagnesium halide.

The addition of the lower alkyl magnesium halide to the last saidcompound of formula 3 is carried out according to the conditions of theGrignard reaction. Convenient and practical conditions for this additioninclude ether or tetrahydrofuran as the solvent for the reaction, areaction time of from five minutes to six hours and a reactiontemperature of from 80 to 25C, preferably 70 to -40C when L of thecompound of formula 3 is radical A and preferably -20 to 0C when L ofthe compound of formula 3 is radical B.

Alternatively, a convenient method for preparing the compound of formula4 in which L is the radical A, R is lower alkyl, R is hydrogen and R ishydrogen or lower alkyl and R" is hydrogen, comprises treating thealdehyde of formula L-CHO in which L is the radical A with a methylketone of formula CI-I COR in which R is lower alkyl, in the presence ofa base, to obtain the corresponding compound of formula 12,

LCI-I=CHCOR followed by treating the latter compound with an appropriatelower alkyl magnesium halide in which the alkyl portion is CR R (CH),,CH in which R", R and n are as defined in the last instance. In thiscase the treatment of the aldehyde with the methyl ketone is performedaccording to the same conditions described hereinbefore for preparingthe compound of formula 12 in which R is CR R -(CI-I ),,CI-I However, inthis case it is advantageous to dispense altogether with an inertsolvent for the reaction and to use a large excess of the ketone offormula CH COR", ie 10 to equivalents, preferably 20 to 60 equivalents.

In other words, it is possible to use the compound of formula 12 in twoways to elaborate the side chain bearing the hydroxy group of thecompound of formula 1. In the case where R of formula 12 is CR R (CH),,CH the R group is the progenitor of part of the hydrocarbon reside ofthe side chain itself and in the case where R is lower alkyl the R groupis 15 the progenitor of the alkyl substituent on the side chainoccurring when R of the compound of formula 1 is lower alkyl.

From this point the process of this invention is completed by one of thefollowing three methods depending on L of the compound of formula 4being the radical, A, B or D.

In the first method when L of the compound of formula 4 is the radicalA, the cyclopropyl compound of formula 4 is condensed with a malonicester derivative in which R and R each are lower alkyl and Z and m areas defined hereinbefore, in the presence of a base. If desired, but notcritical, the hydroxy group of the compound of formula 4 may beprotected during the course of this condensation. Suitably protection isafforded by reacting said last-named compound of formula 4 with theappropriate aforementioned reagent for providing a protected hydroxygroup to afford the corresponding compound of formula 4 in which R is aradical suitable for protecting a hydroxy group, for example, THP, TMS,DMIS or tert-butyl, see above.

The malonic ester derivative of formula 5, noted above, is prepared bycondensing the appropriate aforementioned lower alkyl m-bromoester offormula 9, with a dialkylmalonate, in the presence of an alkali metalalkoxide in a lower alkanol. More particularly, the condensation isperformed preferably by adding the dialkylmalonate portionwise to asolution of one equivalent of sodium methoxide in methanol at atemperature of from 10 to 30C, preferably room temperature. Afterstirring for about 10 to 20 minutes, the reaction mixture is treatedportionwise with one equivalent of the bromoester of formula 9 followedby heating the reaction mixture at reflux temperature for l to 2 hours.Thereafter, dilution of the mixture with water, extraction with awater-immiscible solvent, preferably ether, washing and drying of theextract, followed by removal of the solvent gives a residue, which onpurification by distillation under reduced pressure gives the desiredmalonic ester derivative of formula 5.

Alternatively the malonic ester derivative of formula in which Z is CHCH=CH- is prepared by treating a (2-formylethyl)malonic aciddi(lower)alkyl ester, for example, (2-formylethyl)malonic acid diethylester, D. T. Warner and O. A. Moe, J. Amer. Chem. Soc., 70,3470 (1948),with a triphenylphosphonium bromide of formula in which R and m are asdefined hereinbefore in the presence of an alkali metal hydride,preferably sodium hydride, in an aprotic solvent, preferably dimethylsulfoxide or dimethyl formamide, in the same manner as describedpreviously for the treatment of the aldehyde of formula l .Cl-lO withthe Wittig reagent. In this manner the corresponding malonic esterderivative of formula CH(COOR) CH CH CH=CH(CH COOR in which R, R and mare as defined hereinbefore is obtained. When R of the latter compoundis hydrogen, said latter compound is converted to the correspondingmalonic ester derivative of formula 5 by treatment with a lower alkanol,for example, methanol or ethanol, in the presence of an acid catalyst,for ex- 16 ample, p-toluenesulfonic acid, boron trifluoride etherate ordry hydrogen chloride.

The requisite triphenylphosphonium bromide of forare prepared readily bytreating the appropriate wbromoacid or w-bromoester of formulal Br Cl-l(Cl-l ),,,COOR in which m is as defined hereinbefore withtriphenylphosphine in an inert solvent, for example, benzene, oracetonitrile, at 20 100C for 12 to 24 hours and collecting theprecipitate.

As noted previously the cyclopropyl compound of formula 4 and themalonic ester derivative of formula 5 are subjected to a base catalyzedcondensation to give the cyclopentanonetriester of formula 6. Thiscondensation is performed in the presence of a suitable base, preferablyan alkali metal alkoxide, for example, sodium methoxide. Other suitablebases include sodium ethoxide, potassium tert-butoxide, and sodiumhydride. More specifically, this condensation is conveniently effectedby heating a mixture of about equimolar amounts of the compound offormula 4 and the triester 5 at to 150C, preferably C, for 30 minutes to6 hours, preferably 1 to 3 hours. The reaction mixture is then cooled,neutralized with an acid, for example, acetic acid, and extracted with awater-immiscible solvent, for example, diethyl ether. Evaporation of theextract and purification of the residue by chromatography on silica gelyields the cyclopentanonetriester of formula 6.

Thereafter, in the case where the hydroxy group has been protected by asuitable protecting group, said group is now removed by an agent knownto be effective for removing such a protecting group. In a preferredembodiment the base catalyzed condensation is effected with a compoundof formula 4 in which R is tetrahydropyran-2-yl and thereafter thetetrahydropyran-2-yl protecting group is removed by treating theresulting cyclopentanonetriester of formula 6 (R tetrahydropyran-Z-yl)with acid, for example, hydrochloric acid, aqueous acetic acid orpreferably p-toluenesulfonic acid, in an inert solvent in the presenceof water, preferably methanol-water (9:1). Other agents for removing theprotecting group are discussed hereinafter.

The cyclopentanonetriester 6 is now treated with an alkali metalhydroxide in the presence of water to give the corresponding compound offormula 1 in which m, n, Z, R R and R are as defined in the firstinstance, X and Y together are oxo and R is hydrogen. Preferably thisreaction is done by heating a mixture of the cyclopentanonetriester withan alkali metal hydroxide, preferably sodium hydroxide or potassiumhydroxide, in the presence of water at reflux temperature of the mixturefor a period of 15 minutes to 6 hours, preferably about l to 3 hours.Neutralization of the reaction mixture with acid, for example, 2N HCl,extraction with a water-immiscible solvent, for example, diethyl ether,and subsequent work up of the extract yields an epimeric mixture of thesaid last-named compound of formula 1. If desired the epimers may beseparated at this stage by chromatography on silica gel.

Thereafter, if desired the latter compound is esterified with a loweralkanol containing one to three car- 17 bon atoms, for example,methanol, ethanol or propanol, in the presence of a acid, for example,sulfuric acid, hydrochloric acid or preferably perchloric acid, to givethe corresponding ester compound of formula 1 in which m, M, Z, R R andR are as defined in the first instance, X and Y together are oxo and Ris lower alkyl. Optionally, this esterification can be effected bytreating said latter compound with an appropriate diazoalkane, forexample, diazomethane, or diazoethane.

The second method, utilized when L of the aforementioned compound offormula 4 is the radical B, proceeds by treating the said compound offormula 4 with an agent known to be effective for removing a radicalsuitable for protecting a hydroxy group. In a preferred embodiment, L ofthe aforementioned compound of formula 4 is the radical B in which R isthe TMS radical. The TMS radical is removed by treatment with an excessof water-methanol (10:1) for 24 hours or with tetrahydrofuran-aceticacid at room temperature for one to two hours. Alternatively, if R isDMIS,

this protecting group is removed by the same conditions used for theremoval of the TMS radical.

In this manner the compound of formula 1 in which m, n, Z, R ,R and Rare as defined in the first instance, X is hydroxy, Y is hydrogen and Ris lower 25 alkyl is obtained. This compound is obtained thus as amixture of epimers with respect to the hydroxy group of the cyclopentanering. If desired the epimers can be separated readily by chromatography.

Furthermore, if so desired, the latter compounds of formula 1 in which Ris lower alkyl are treated with an oxidizing agent capable of convertinga hydroxy function to the corresponding keto function to yield thecorresponding compound of formula 1 in which X and Y together are oxo.Suitable oxidizing agents include chromium trioxide-pyridine complex,chromium trioxide-sulfuric acid in acetone, with the former beingpreferred.

The third method, utilized when L of the compound of formula 4 is theradical D and R is hydrogen proceeds with preferential hydrolysis of theketal. The hydrolysis is effected by treatment with an acid in thepresence of water, in an inert solvent. Suitable conditions for thishydrolysis include the use of p-toluenesulfonic acid or acetic acidatatemperature of from 25 to 100C using tetrahydrofuran, dioxane,acetone or methanol as the solvent and a reaction period of from threeto 24 hours. Preferably, the hydrolysis is effected usingp-toluenesulfonic acid in tetrahydrofuran or a mixture of water andmethanol at room temperature for 12 to 24 hours.

In this manner the compound of formula 1 in which m, n, Z, R and Rare-as defined in the first instance, X and Y together'are oxo, R islower alkyl and R is hydrogen is obtained.

Finally, and if desired any of the aforementioned compounds of formula 1in which X and Y together are 0x0 and R is lower alkyl are reduced bytreatment with a complex borohydride to give the corresponding compoundof formula 1 in which X is hydroxy and Y is hy- 18 at to 0C, preferably80 to 60C, for l to 2 hours. In this instance the resulting compound offormula I in which X is hydroxy and Y is hydrogen and R is hydrogen orlower alkyl is obtained as a mixture of epimeric C-2 alcohols. Thismixture is conveniently separated into its individual C-2 alcoholepimers by chromatography on silica gel.

The following examples illustrate further this invention- EXAMPLE 1Dimethyl 3,3-dimethyl-2-oxoheptyl phosphonate [(AlkO) POCl-l COCR R (CH),,CH in which Alk is CH R and R CH and n 3] The title compound isprepared by treating 2,2-dimethylhexanoic acid methyl ester, S. M.McElvain, et al., J. Amer. Chem Soc., 75, 3987 (1953), with dimethylmethyl phosphonate according to the procedure of E. J. Corey and G. T.Kwiatkowski, J. Amer. Chem. Soc., 88, 5654 (1966). An exemplification ofthis procedure is as follows:

Dimethyl methylphosphona'te (14.88 g) is dissolved in drytetrahydrofuran (THF, 34 ml) under a nitrogen atmosphere. The solutionis cooled to 78C. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3equiv.) is added very slowly during 1 hour. The mixture is stirred at78C. for 15 minutes. A solution of 2,2-dimethylhexanoic acid methylester (6.32 g) in dry THF (16 ml) is added to the cold solution over aperiod of 1 hour. The mixture is stirred for 30 minutes and then allowedto warm up to room temperature. The reaction mixture is diluted withether. Dilute (10%) hydrochloric acid (30 m1) is added and the reactionmixture shaken well. The organic phase is separated and washed severaltimes with water, dried (MgSO and the solvent removed. The residue isdistilled under reduced pressure to give the title compound, b.p. 1 10C/0.1mm, 'y 1700, 1250, 1020 cm".

Similarly other Wittig reagents of the formula (A1- kO) POCI-I COCR R-(CH ),,CH in which Alk is an alkyl containing 1 to 3 carbon atoms, Rand R are hydrogen or lower alkyl and n is an integer from 2 to 5 areprepared by using the appropriate lower alkyl alkanoate anddi(1ower)alkyl methanephosphonate. For instance, treatment of2,2-dipropylpentanoic acid methyl ester with dimethyl methylphosphonategives 2-oxo- 3,3-dipropylhexyl phosphonate and treatment of 2,2-diethyloctanoic acid ethyl ester with diethyl methylphosphonate gives2-oxo-3,I3-diethylnonyl phosphonate.

EXAMPLE 2 Dimethyl 2-formylcyclopropane-1 l-dicarboxylate (2; L=-radical A in which R CH;,)

65 11-1), is obtai'rie Lilge'wise the of dipropylbromomalonate and Bit)anol gives iiipiopyl 2-formylcyclopropane-l,1-dicai= ax late.

EXAMPLE 3 Diethyl trans-2-(4,4-dimethyl-3-oxo-l-octenyl)cyclopropane-1,1-dicarboxylate (3; R and R CH n 3 and L radical A in which R C H To asuspension of 50% sodium hydride (0.46 g, washed with hexane) indimethylformamide (DMF) is added a solution of dimethyl3,3-dimethyl-2-oxoheptyl phosphonate (2.75 g), described in Example 1,in DMF ml) over a period of min. The mixture is stirred and cooled inice water during the addition and for an additional period of min. Asolution of diethyl 2-formylcyclopropane-l,l-dicarboxylate (2.14 g) inDMF (15 ml) is added over 20 min. The reaction mixture is heated at to Cand stirred for 45 min. The mixture is now cooled in an ice bath andacetic acid is added to render the mixture substantially neutral. Thereaction mixture is poured into water (4 X the volume) and the resultingoily precipitate extracted with ether. The extract is washed with water,dried (Na SO and concentrated. The residue is dissolved in ethylacetatebenzene (1:9) and the solution poured through a column of silicagel (148 g). The eluate is concentrated to yield the title compound, 'y1725, 1680, 1620 cm, nmr (CDCI 8 0.88 3H), 4.27 (4H), 6.5, 6.68 and 7.39(m, 2H), 'y fi' 242 nm (e 7500).

20 1665, 1620 cm", nmr (CDCl 8 4.19 (q, J 7, 4H), 6.32 (d, J 5, 2H), isobtained.

In the same manner but replacing dimethyl 3,3- dimethyl-Z-oxoheptylphosphonate with an equivalent amount of dimethyl 2-oxoheptylphosphonate, described by E. J. Corey, et al., J. Amer. Chem. Soc., 90,3247 (1968), diethyltrans-2-(3-oxo-l-octenyl)cyclopropane-1,l-dicarboxylate, b.p. 153154C/0.7 mm, is obtained.

In the same manner but replacing dimethyl 3,3-dime'thyll2-oxoheptylphosphonate with an equivalent amount of dimethyl3-ethyl-2-oxohexyl phosphonate, dimethyl 3-propyl-2-oxooctylphosphonate, or dimethyl 3-ethyl-2-oxononyl phosphonate, dimethyltrans-2-(4-ethyl-3-oxo-l -heptenyl)cyclopropane-l ,1- dicarboxylate,dimethyl trans-2-(3-oxo-4-propyl-lnonenyl)cyclopropane-1,l-dicarboxylateand dimethyl trans -2-(4-ethyl-3-oxo-l-decenyl)cyclopropane-1,1-dicarboxylate are obtained, respectively.

By following the procedure of Example 3 and utilizing the appropriateWittig reagent and the aldehyde of formula L-CHO in which L is theradical A wherein R is lower alkyl then other compounds of formula 3 areobtained. Examples of such compounds of formula 3 are listed in Table 1together with the appropriate Wittig reagent and aldehyde of formulaL-CHO utilized for their preparation.

TABLE I Wittig Reagent Product: (Prefix Listed L-C HO below)-cyclopropane EX. (Alko )POCH,COCRR-(CH ).CH L radical ALl-dicarboxylate Alk R R n R 4 CH; H 2 CH, dimethyltrans-2-(3-oxol-heptenyl) 5 CH H 4 C H diethyl trans-2-(3-oxol-nonenyl)6 CH, H 5 CH dimethyl trans-2-(3-oxol-decenyl) 7 CH CH; H 2 C,H diethyltrans-2-(4- methyl-S-oxol -heptenyl) 8 CH CH H 4 CH dimethyl trans-2-(4-methyl-3-oxo-l-nonenyl) 9 CH Cg; H 3 C H, diethyl trans-2-(4-ethyli3-oxo-1-octenyl) 10 CH, C H H 5 CH dimethyl trans-2-(4- Y ethyl-3 -oxol-decenyl) 11 CH; n-C,H H 2 C,H, diethyl trans-Z-(B-oxo-4-propyl-l-heptenyl) 12 CH: n-C,H-, H 4 CH, dimethyl trans-2(3-oxo-4-propyl-l-nonenyl) 13 C,H,-, CH, CH, 5 n-C H dipropyl trans-2-(4,4-

dimethyI-3-oxo-l-decenyl) 14 C,H C,H CH, 5 n-C H dipropyltrans-2-(4-ethyl- 4-methyl-3-oxo-ldecenyl) 15 C2; n-C,H CH, 2 CH;dimethyl trans-2-(4- methyl-3-oxo-4-propyl-lheptenyl) 16 C3"; n-C,H-,n-C,H 4 C,H, diethyl trans-2-(3-oxo-4,-

' 4-dipropyl l-nonenyl) EXAMPLE 17 Diethyltrans-2-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopropane-l,l-dicarboxylate (4; R and R H, R and R CH n 3 and Lradical A in which R Sodium borohydride (0.19 g) is added to a solutionof diethyltrans-2-(4,4-dimethyl-3-oxo-l-octenyl)cyclopropane-l,l-dicarboxylate(1.62 g), described in Example 3, in ethanol (2.5 ml) at 0 to 5C. Afterthe addition the mixture is rendered neutral by the addition of aceticacid, diluted with ether and washed with water. The ether phase is dried(Na SO and concen- 21 trated. The residue is dissolved in ethylacetate-benzene (1:9) and the solution poured through a column of silicagel (50 g). The eluate is concentrated to give a title compound, y 3500,1706 cm, nmr (CDCI 8 2.6 (in, 11-1), 3.78 (m, 1H), 4.21 (q, 41-1), 5.28(q, 1H), 5.9 (q, 1H).

In the same manner but replacing diethyl trans-2- (4,4-dimethyl-3-oxol-octenyl )cyclopropane-l l dicarboxylate with an equivalent amount ofdiethyl trans-2-(4-methyl-3-oxol -octenyl) cyclopropane-lldicarboxylate, described in Example 3, diethyl trans-2-(3-hydroxy-4-methyl-l-octenyl)cyclopropane-1,1- dicarboxylate, 'y 3500cm, is obtained.

By following the procedure of Example 17 and utilizing the appropriatecompound of formula 3 then other compounds of formula 4 (R H) areprepared. Examples of such compounds of formula 4 are listed in TableII. In each case the compound of formula 3 used as starting material isnoted by the Example in which it is prepared.

TABLE II is diluted with water and extracted with 1500 ml ether. Theether layer is washed with saturated NaCl solution twice, then withsodium thiosulfate solution twice, again with saturated NaCl solution,dried (Na SO and concentrated to give a greenish yellow oil. The oil isdissolved in ethyl acetate-benzene (3:17) and poured through a column ofsilica gel. The eluate is concentrated to yield the title compound, nmr(CDCl 8 0.88 (t, J 5, 3H), 2.45 (q, 2H), 4.13 (q, 2H), 5.14 (2Xd, J16.8, 1H), 5.72 (d, J =16, III).

In the same manner but replacing methyl magnesium iodide with anequivalent amount of ethyl magnesium chloride, or propyl magnesiumbromide, diethyl trans- 2-(3-ethyl-3-hydroxy-l-octenyl)cyclopropane-l,1- dicarboxylate and diethyl trans-2-(3-hydroxy-3-propyl- 1-octenyl)cyclopropane-l ,1 -dicarboxylate, are obtained, respectively.

In the same manner but replacing diethyl trans-2-(3-oxo-l-octenyl)cyclopropane-l ,l-dicarboxylate with an equivalent amountof diethyl trans-2-(4-methyl-3-oxo- PRODUCT: (PREFIX LISTED NO. OFEXAMPLE IN WHICH STARTING BELOW) CYCLO- 1 -octenyl)cyclopropane-1 ,1-dicarboxylate, described in Example 3 andusing methyl magnesium iodode,ethyl magnesium chloride or propyl magnesium bro- EXAMPLE MATERIAL OFFORMULA 3 IS PROPANE-1,l-DICARBOXYLATE PREPARED l8 3 dimethyltrans-2-(4-ethyl- 3-hydroxy1-heptenyl) l9 3 diethyl trans-2-(3hydroxy-4-propyl -l-nonenyl) 3 dimethyl trans-2-( 4-ethyl 3-hydroxyl -decenyl)21 7 diethyl trans-2-(3-hydroxy- 4-methyl-l'heptenyl) 22 8 dimethyltrans-2-(3-hydroxy- 4rnethyll 'nonenyl) 23 9 diethyl trans-2-(4-ethyl-3-hydroxy- 1 -octenyl) 24 1O dimethyl trans-2-(4-ethyl-3- hydroxy- 1-decenyl) 25 l 1 diethyl trans-2-(3-hydroxy-4- propyl-l-heptenyl) 26 12dimethyl trans-2-(3-hydroxy- 4-propyl-1-nonenyl 27 13 dipropyltrans-2-(3-hydroxy- 4,4-dimeth yll -decenyl) 28 14 dipropyltrans-2-(4-ethyl- 3-hydroxy-4-methyl-l-decenyl) 29 15 dimethyltrans-2-(3-hydroxy- 4-methyl-4-propyl-l-heptenyl) 30 16 diethyltrans-2-(3-hydroxy-4,-

4-dipropyl-l-nonenyl) EXAMPLE 31 Diethyl trans-2-( 3-hydroxy-3-methyl- 1-ocetnyl )cyclopropane- 1,l-dicarboxylate (4; R CH R, R and R H, n 3 andL radical A in which R C H A solution of the lower alkyl magnesiumhalide,

methyl magnesium iodide, prepared from 24.31 g of 60 magnesium turningsand 157 g of methyl iodide in 1000 ml of ether, is cooled to -70C.Diethyl trans-2-(3-oxol-octenyl)cyclopropane-l,l-dicarboxylate (124.2g); described in Example 3, in 600 ml ether is added slowly taking carethat reaction mixture temperature does not exceed C. The mixture isstirred 75 min. at the temperature range to -45C. Aqueous saturated NHCI solution is added slowly keeping the temperature of the reactionmixture below C. The mixture mide as the lower alkyl magnesium halide,diethyl trans-2% 3-hydroxy-3 ,4-dimethyll -octenyl)cyclopropane-1,1-dicarboxylate, diethyl trans-2-(3-ethyl-3-hydroxy-4-methyl-l-octenyl)cyclopropane-1,l-dicarboxylate and diethyltrans-2-(3-hydroxy-4-methyl-3propyl-1-octeny1)cyclopropa'ne-l,l-dicarboxylate, are obtained,respectively.

By following the procedure of Example 31 and utilizing the appropriatelower alkyl magnesium halide and compound of formula 3, for examplethose described in Examples 4 to 12, then other compounds of formula 4in which R is lower alkyl are obtained. Examples of such compounds offormula 4 are listed in Table III together with the requisite loweralkyl magnesium halide and the compound of formula 3.

TABLE III NO. OF EXAMPLE IN WHICH STARTING MATERIAL OF FORMULA 3 ISLOWER ALKYL EXAMPLE MAGNESIUM HALIDE PRODUCT:

(PREFIX LISTED BELOW )-CYCLOPROPANE- l,l-DICARBOXYLATE PREPARED 32 4 CHMgl dimethyl trans-2-(3- hydroxy-3-methyI-lheptenyl) diethyl trans-2-(3-ethyI-3-hydroxyl nonenyl) dimethyl trans 2-(3-hydroxy-3-propyl-ldecenyl) diethyl trans2-(3- hydroxy-3,4-dimethyll-heptenyl) dimethyl trans-2-(3- ethyI-3hydroxy4- methyl-l-nonenyl)diethyl trans2-(4- ethyl-3-hydroxy-3- propyll -octenyl) dimethyItrans-2-(4- ethyl3-hydroxy-3- methyl-l -decenyl) diethyl trans2-(3-ethyl-3-hydroxy-4- propyl l -heptenyl) dimethyl trans'2-(3-hydroxy-3,4-dipropyllnonenyl) EXAMPLE 4l Diethyltrans-2-{3-[(tetrahydropyran-Z-yl)oxy]-3'methyl-loctenyl}cycIopropane-l,l-dicarboxylate (4, R CH R and R H, R (tetrahydropyran-Z-yl)oxy, n 3and L radical A in which R C I-I A solution of diethyltrans-2-(3-hydroxy-3-methyl-loctenyI)cyclopropane-l,l-dicarboxylate(22.4 g), described in Example 31, dihydropyran (80 ml, distilled oversodium) and p-toluenesulfonic acid monohydrate (300 mg) is allowed tostand at room temperature for min. After adding a few ml of 10% Na COsolution the mixture is extracted with ether. The ether extract iswashed with water, dried (Na SO and evaporated. Purification of theresidue by chromatography on silica gel gives the title compound, nmr(CDCl 8 0.87 (t, 3H), 2.48 (m, 1H), 4.6 (1H), 5.5 (m, 2H).

In the same manner but using an equivalent amount of one of thecompounds of formula 4 (R H), for example, the compounds listed inExamples 17 to 40, instead of diethyltrans-2-(3hydroxy-3-methyl-loctenyl)cyclopropane-l,l-dicarboxylate, thenthe corresponding tetrahydropyranyl ether compound of formula 4 (Rtetrahydropyranyl) is obtained, for example, the correspondingtetrahydropyranyl ethyl compounds of Examples 17 to 40, respectively.More specifically exemplified, in the same manner diethyl trans- 2-(3-hydroxy-4-methyll -octenyl )cycIopropane-l l dicarboxylate, describedin Example 17 gives diethyl trans-2-{3-[(tetrahydropyran-2-yl)oxy]----methyl- 1 -octenyl} -cyclopropane-l 1-dicarboxylate, S 1035, 1140, 1220cm, and dimethyl trans-2- (4-ethyl-3-hydroxyl -decenyl)cyclopropanel l-dicarboxylate, described in Example 24, gives dimethyltrans-2-{4-ethyl-3-[ tetrahydropyran-Z-yl )oxy]- l decenyl}cyclopropane-l l -dicarboxylate.

EXAMPLE 42 Trimethyl cis-3-heptene-l,l,7-tricarboxylate (5, R and RCH;;, Z -CH CHCH and m 2) Dimethyl malonate (39.6 g) is added slowlywith cooling and stirring to a solution of 6.9 g of sodium dissolved inml of absolute methanol and the mixture stirred for 15 min. Thebromoester of formula 9, methyl cis-7-bromo-5-heptenoate (65.7 g) isadded dropwise. The mixture is heated at reflux for 1 hr., cooled anddiluted with water. The mixture is extracted with ether. The etherextracts are dried (Na SO', and concentrated. The residue is distilledunder reduced pressure to give the title compound, b.p. l50C/0.7 mm.

The title compound is also described in copending application Serial No.238,650, filed Mar. 27, 1972.

In the same manner but replacing methyl cis-7- bromo-S-heptenoate withan equivalent amount of methyl 7-bromo-4-heptenoate, methyl6-bromo-4-hexenoate, methyl 6-bromo-3-hexenoate, methyl 5-bromo-3-pentenoate, methyl 5-bromo-2-pentenoate, methyl 7-bromoheptanoate,methyl 6-bromohexanoate or methyl 5-bromohexanoate, trimethyl4-heptene-l,l,7- tricarboxylate, trimethyl3-hexene-l,l,6-tricarboxylate, trimethyl 4-hexene-l,l ,6-tricarboxylate,trimethyl 3-pentene-l,l,5-tricarboxylate, trimethyl 4-pentenel l,S-tricarboxylate, trimethyl heptane-l l ,7-carboxylate, trimethylhexane-l,l,6-tricarboxylate and trimethyl pentane-l,1,5-tricarboxylateare obtained, respectively.

By using the corresponding ethyl or other lower alkyl ester analogs ofthe methyl ester starting materials noted above, the corresponding ethylor other lower alkyl esters of the methyl ester proudcts, noted above,are obtained.

The following example discloses an alternative preparation of the above"A triesters of formula V.

EXAMPLE 43 Triethyl cis-4-heptene-1,l,7-tricarboxylate (5, R and R C H Z=CH CH=CH- and m 2) For the following reaction, butyric acidtriphenylphospll onium bromide, m.p. 245 246C, is prepared by treating-y-bromobutyric acid (100 g) with triphenyl phosphine in benzene (630ml) at reflux temperature for 16 hr. and recrystallizing the resultingprecipitate from ethanol.

Sodium hydride (50%, 19.46 g) is dissolved in dimethylsulfoxide (404 ml)with warming (70 80C) under a nitrogen atmosphere. The solution iscooled to 15 to 20C. A solution of butryic acid triphenylphosphoniumbromide (86.99 g) in dimethylsulfoxide is added. The mixture is stirredat the latter temperature for 5 min. and then treated dropwise with(2-formylethyl)malonic acid diethyl ester (39.7 g), described by Warnerand Moe, cited above, over a period of 20 min. The mixture is stirred atroom temperature for 2 /2 hr. and then cooled 20C) and rendered acidicwith acetic acid (60 ml). The reaction mixture (pH about 6) is pouredinto 2% liters of ice water. After extraction with ether (2x), theaqueous layer is rendered acidic with concentrated hydrochloric acid topH 3 and ex tracted with ether (2x). The ether extracts are combined andwashed with water (2x), then extracted with 10% Na CO solution (3 X 200ml). The aqueous so dium carbonate extracts are washed with ether (2x)and rendered acidic with cone HCl to pH 5. The acidic solution isextracted with ether (2x). The ether extracts are washed with water,dried and concentrated to dryness to give 1,1-diethylcis-4-heptene-1,l,7-tricarboxylate.

The latter compound (21.4 g) in absolute ethanol (214 ml) is heated atreflux with p-toluenesulfonic acid (0.214 g) for 20 hr. After cooling toroom temperature the reaction mixture is treated with 4 ml of pyridineand then diluted with water (750 ml). The mixture is extracted withether. The ether extract is washed with water, dried (MgSO andconcentrated to give the title compound, 'Ymar 1735 cm.

In the same manner other A -triesters of formula 5, namely triethyl4-hexene-1,1,6-tricarboxylate and triethyl4-pentene-l,1,5-tricarboxy1ate, are prepared by replacing butyric acidtriphenylphosphonium bromide with propionic acid triphenyl phosphoniumbromide and acetic acid triphenyl phosphonium bromide, respectively.

EXAMPLE 44 Dimethyl cis,trans-3-(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo1 ,3-cyclopentanedicarboxylate (6, m =2, n3, Z CH=CHCH R R,

R, R and R CH, and R and R H) To a solution of trimethylcis-3-heptene-1,1,7-tricarboxylate (1.36 g), described in Example 42, in3 ml of methanol, a freshly prepared solution of sodium methoxide (from0.126 g of sodium and 6 ml of absolute methanol) is added. The mixtureis heated to 80C. A solution of dimethyltrans-(4,4-dimethyl-3-hydroxy-1- octenyl)cyclopropane-1,l-dicarboxylate(1.7 g) is gradually added to the mixture and the resulting mixturestirred for an additional min. The methanol is removed by distillationat reduced pressure. The residue is then heated at 100C for 45 min.Thereafter the 5 tate-benzene (1:4) as eluant gives the title compound,

nmr (CDCl 8 0.88 (3Xm, 9H), 3.68 3.8 (3Xm, 9H), 5.5 (2Xm, 4H).

EXAMPLE 45 Diethyl cis, trans-3-(6-carboethoxy-2-hexenyl)-4(3-hydroxy-3-methyl-1-0ctenyl)-2-oxo-1 ,3-cyclopentaedicarboxylate (6, m 2, n 3, Z-CH=CHCH R, R and R C H R CH R R and R H) To a mixture of the compoundof formula 4, diethyl trans-2- 3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl cyclopropane-l,l-dicarboxylate (20.4 g), described in Example41, and the compound of formula 5, triethylcis-3-heptene-1,1,7-tricarboxylate (15.08 g), described in Example 42, asolution of 1.27 g of sodium in 50 ml of methanol is added at roomtemperature. The methanol is removed under slightly reduced pressure.The residue is heated at C for 1 hr. while keeping a slightly reducedpressure in the reaction flask. Saturated NaCl solution is added and themixture rendered neutral with acetic acid. The mixture is extracted withether. The extract is dried (Na SO and concentrated. Chromatography ofthe residue on silica gel [eluant ethyl acetate-benzene (1:4)] yieldsdiethyl cis, trans-3-(6-carboethoxy-2-hexenyl)-4-{3-[(tetrahydropyran-Z-yl)oxy]-3-methyl-l-octenyl -2-}oxo-l,3-cyclopentanedicarboxylate, S 291 nm e 13,400) in the presence ofbase (NaOH).

A solution of the latter compound (10.5 g) in 80 ml of methanol-water(9:1) and 1.0 g of p-toluenesulfonic acid monohydrate is left at roomtemperature for 15 min. and then rendered neutral with aqueous NaHCO Themethanol is evaporated and after addition of saturated NaCl, the mixtureis extracted with ether. The ether layer is dried (Na SO Evaporation ofthe solvent gives a residue, which on purification by chromatography onsilica gel affords. the title compound, nmr (CDCl;,) 8 0.84 (t, J=6,3H),.1.22(2 m, 6H), 4.16 (m 6H), 5.35 (m, 2H), 5.56 (m, 2H).

By following the procedures of Examples 44 and 45 and using theappropriate compounds of formulae 4 and 5 as starting materials, othercyclopentanoetriesters of formula 6 are obtained.

For example, the use of the compound of formula 4, diethyltrans-2-{3-[(tetrahydropyran-Z-yl)oxy]-3- methyl-l-octenyl}cyclopropane-l ,l-dicarboxylate, described in Example 41, and thecompound of formula 5, triethyl heptane-l,1,7-tricarboxylate, describedin Example 42, in the procedure of Example 45 gives diethyltrans-3-(6-carboethoxyhexanyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, 'y 3500, 1725cm", nmr (CDCl;,) 8 0.88 (t, 3H), 4.17 (m, 6H), 5.64 (m, 2H), via theintermediate diethyltrans-3-(6-carboethoxyhexanyl)-4-{3-[(tetrahydropyran-2-y1)oxy]-3-methyl-l-octenyl}-2-oxo-1,3-cyclopentanedicarboxylate, S 1730 cm".

Likewise, the use of diethyltrans-2{3-[(tetrahydropyran-2-yl)oxyl-4-methyl-1-octenyl}-cyclopropane-1,1-dicarboxylate and triethyl cis-3-heptene-1,1,7- tricarboxylate givesdiethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-4-methyl-1-octenyl)-2-oxo-l ,3-cyclopentanedicarboxylate, 'y f' 3500 TABLE III-continued NO.OF EXAMPLE (6-carbomethoxy-3- hexenyl )-4-( 3-hydroxy- 3,4-dipropyl- I-nonenyl) EXAMPLE 68 trans,cis-7-[2-(3-l-lydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]--heptenoicAcid (1, m 2, n 3, X and Y 0, Z CH=CHCH R, R and R H and R 3) Thecyclopentanonetriester of formula 6, diethyl cis,- trans-3-(6-carboethoxy-2-hexenyl )-4-( 3-hydroxy-3- methyl-l-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (11.2 g), described in Example 45, isheated to reflux for 1 hr. in a solution of sodium hydroxide (13.4 g) in80 ml of water and 1 10 ml of methanol. The mixture is cooled, adjustedto pH 5 with 2N HCl, diluted with saturated sodium chloride solution andextracted with ether. The ether extract is dried (Na SO andconcentrated. Chromatography on silica gel yields the title compoundV,,,,, 3 3580, 1740, 1720 cm, nmr

methyl- 1 -octenyl )-5-oxocyc1opentyl heptanoic acid, nmr (CDCI 5 0.88(t, 3H), 5.52 (m, 2H), 6.6 (broad singlet, 2H).

Likewise, the use of diethyl cis, trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-4-methyll -octenyl -2- oxo-1,3-cyc1opentanedicarboxylate,described in Example 45, gives trans; cis-7-[2-(3-hydroxy-4-methyl-1-octenyl)-5-oxocyclopentyl]S-heptenoic acid, 'ymux 3450, 1725, 1710 cm.

Likewise, the use of diethyl cis,trans-3-(6-carboethoxy-3-hexeny1)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-l,3-cyclopentanedicarbo xylate, described in Example 45, givestrans, cis-7-[2-(3-hydroxy-3-methyl-loctenyl)-5-oxocyclopentyl]-4-heptenoic acid, 'y3620, 3000, 1740, 1720 cm, nmr (CDCI 8 0.89 (t, J 5, 3H), 2.4 (4H), 5.4(m, 2H), 5.65 (m, 2H), 5.9 (broad sinlet, 2H).

Likewise, the use of dimethyl cis,trans-3-(6-carbomethoxy-2-hexenyl)-4-( 3-hydroxy-4,4-dimethyl- 1octenyI)-2-oxo-1 ,3-cyc1opentanedicarboxylate, described in Example 44,gives trans, cis-7-[2-(3- hydroxy-4 ,4-dimethyl- 1 -octenyl)-5-oxocyclopentyl -5- heptenoic acid, 'y 3400 3000, 1730, 1710 cm, nmr(CDCl;,) 8 0.85 (m 9H), 3.9 (m, 1H), 5.42 (m, 2H), 5.68 (m, 2H), 6.75(broad s, 2H).

Further examples of such compounds of formula 1 are listed in Table IVtogether with the requisite cyclopentanonetriesters starting material,the latter compound being noted by the example describing itspreparation.

TABLE IV NO. OF EXAMPLE IN WHICH CYCLOPENTANONETRIESTER EXAMPLE OFFORMULA 4 IS PRODUCT:

TABLE IV-continued PREPARED pentyll-S-heptenoic acid trans.cis-6-l2-(4-ethyl-3- pentyl l-3-hexenoic acid trans- 2-( 4-ethyl-3-hydroxyl-decenyl )-5-oxocyclopentyl] pentanoic acid trans.cis-6-[2-(3-hydroxy-4- pentyl]-4-hexenoic acid pentyl I-4-heptenoic acidtrans-6-[2-(4,4-dimethyl-3- hydroxy-1-decenyl)-5-oxocyclopentyllhexanoic acid trans, cis-5-[2-(4-ethyl-4- methyl-3-hydroxyl -decenyl)-5- oxocyclopentyll-3-pentenoic acid trans, cis-6-[2-(4-methyl-3-trans-7-[ 2-( 3-hydroxy-4,4-dipropylheptanoic acid 59 trans-74 2-(3-hydroxy-3-methyl' l-heptenyl )-5-oxocyclopentyl heptanoic acid trans,cis-6-[ 2( 3-ethyl-3-hydroxy- 4-hexenoic acid trans. cis-5-l 2-(3-hydroxy-3 propyll-decenyl )-5-oxo cyclopentyl ]-2-pentenoic acid 85trans-6-l 2-( 3-hydroxy-3 ,4dimethyll-heptenyl )-5-oxocyclopentylhexanoic acid trans,cis-7-[ 2-( 3-ethyl-3 -hydroxypentyll-S-heptenoicacid pentyll-B-hexenoic acid trans-5 2-( 4-ethyl-3-hydroxypentyllpentanoic acid trans,cis-6l2-( 3-ethyl-3-hydroxy- 4-propyll heptenyl)-5-oxocyclopentyl ]-4-hexenoic acid trans,cis-7-[ 2-( 3-hydroxy-3 ,4-

pentyl ]-4-heptenoic acid EXAMPLE 91 Methyl trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-1-octeny1)-5-ox0cycl0pentyl]-5-heptenoate 1; m =2, n 3, X and Y 0, Z CH=CHCH R R and R CH and R H) Thecompound of formula 1, trans,cis-7-[2-(3- hydroxy-4, 4-dimethyl-1-octenyl)-5-oxocyclopentyl]- S-heptenoic acid (11.1 g), describedin Example 68, is dissolved in 44 ml of absolute methanol containing 2%perchloric acid. The solution is kept at room temperature for min.Thereafter the mixture is rendered neutral with 10% Na CO andconcentrated. The residue is diluted with water and shaken with ether.The ether layer is washed with water, dried (MgSO and concentrated yieldthe title compound, y 3600 3400, 1730, 1710 cm.

The latter compound is a mixture of epimers with respect to theasymmetric carbon to which the hydroxy group is attached, each epimerbeing a racemate consisting of a d 1 pair of stereochemical isomers. Bysubjecting the preceding product to chromatography on silica gel usingethyl acetate-benzene (1:4) as eluant,

the product is separated into its two epimeric forms which arearbitrarily designated lsomer A (least polar isomer) and lsomer B (mostpolar isomer); the polarity being determined by the order in which theseepimers are eluted. lsomer A: 'Ymax 3470, 1730 cmnmr (CDC1 8 0.85 (9H),3.68 (s, 31-1), 3.82 (m, 1H), 5.4 5.7 (m, 41-1), Rf=0.88 on thin layerplates of silica gel when using ethyl acetate-benzene (2:3) as themobile phase.

lsomer B: y 3470, 1730 cm, nmr (CDCl 8 3.67 (s, 31-1), 3.82 (m, 1H),5.41 (m, 2H), 5.66 (m, 2H), Rf= 0.69 on thin layer plates of silica gelwhen using ethyl acetate-benzene (2:3) as the mobile phase.

In the same manner but using the appropriate choice of the compound offormula 1 and lower alkanol, other corresponding esters of formula l (Rlower alkyl) are prepared; for example, the corresponding lower alkylesters of the products of Table 1V. More specifically exemplified, thechoice of trans-7-[2-(3-hydroxy- 3 -methyl- 1 -octenyl )-5-oxocyclopentyl ]heptanoic acid, described in Example 68, as the compoundof formula 1 and methanol as the lower alkanol in the procedure of thisexample give methyl trans-7-[2-(3-hydroxy-3- 33 methyl- 1-octenyl)--oxocyclopenthyl]heptanoate, 'y 3475, 1730 cm", nmr (CDCl 80.89 (t, 3H), 3.64 (s, 3H), 5.61 (m, 2H).

Likewise, the choice of trans.cis-7-[2-(3-hydroxy-3- methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid described in Example 68,and methanol, gives methyl trans, cis-7[2-( 3-hydroxy-3-methyl- 1-octenyl )-5- oxoclyclopentyl]-5-heptenoate, y,,,,,,"" 1738, 1730 cmLikewise, the choice of trans,cis-7-[2-(3-hydroxy-4- methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid and methanol gives methyltrans, cis-7-[2-( 3-hydroxy- 4-methyl- 1 -octenyl )-5 -oxo cyclopentyl]-5 -heptenoate, y 1732 cm ,nmr (CDCl;,) 8 3.65 (s, 3H), 5.25 5.75 (m,4H).

Likewise, the choice of trans, cis-7-[2-(3-hydroxy-3- methyl- 1-octenyl)-5-oxocyclopentyl]-4-heptenoic acid and ethanol gives ethyltrans, cis-7-[2-(3-hydroxy-3- methyl- 1-octenyl)-5-oxocyclopentyl]-4-heptenoate, y 1740, 1732 cm.

EXAMPLE 92 Methyl trans, cis-7-[ 2-hydroxy-5-( 3-hydroxy-4,4-dimethylloctenyl)cyclopentyl]-5-heptenoate (1; m 2, n 3, X OH, Y H, Z CH=CHCH R,R and R CH,

and R H) r A solution of borane (11 ml of 1M soln.) in THF is added to asolution of pinene (2.99 g) in dry diglyme (8.0 ml) at C (bath temp.) ina N atmosphere. The mixture is stirred for 10 min. then cooled to -78C.To this mixture tert-butyl lithium (5.5 ml, 2.1 molar in pentane) isadded slowly, maintaining the temp. of the reaction at -78C. Afterstirring for 10 min., a solution of methyl trans, cis-7-[2-(3-hydroxy-4,4-dimethyl-l-octenyl)-5-oxocyclopentyl]-5-heptenoate, Isomer B (1.37g), described in Example 91, in diglyme-THF (8.8 ml, 1:07) is added tothe mixture. The temperature is maintained at 78C for 1 hour. Thecooling bath is removed and, the reaction is quenched by adding 10%sodium hydroxide solution (8 ml) and 30% hydrogen peroxide solution (8ml). The mixture is then diluted with water and extracted with ether.The ether extract is washed with water and 3% HC] soln. to render itneutral, dried (MgSO and concentrated to yield the title compound(lsomer B) 'y fl'" 3600 -3440, 1730 1720 cm. This product is a mixtureof epimerswith the respect to the asymmetric carbon of the'cyclopentanering to which the hydroxy group is attached, each epimer being aracemate consisting of a d 1 pair of stereochemical isomers. The productis separated into these two epimers by subjecting it to chromatographyon silica gel (135 g) using ethyl acetate-benzene 1:4) as eluant. Inthis manner the product is separated into a first epimer (less polar)and a second epimer (more polar):

Less polar epimer y 3400, 1730 1720 emf, nmr (CDCl;,) 8 0.88 (m, 9H),3.68 (s, 3H), 3.79 (m, 1H), 4.2m, 1H), 5.5 (m, 4H), Rf= 0.52 on thinlayer plates of silica gel when using ethyl acetaterbenzene (2:3) as themobile phase. v

More polar epimer y,,,,,,"" 3400, 1726 cm, nmr (CDCl,,) 8 0.88 (m, 9H),3.67 3.95 (m, 5H), 5.52 (m, 4H), Rf 0.41 on thin layer plates of silicagel when using ethyl acetate-benzene (2:3) as the mobile phase.

Comparative date with the nmr spectra of known hydroxyprostaglandinderivatives, for example see I. F.

Bagli and T. Bogri, Tetrahedron Letters, 1639 (1969), and the order ofelution of known hydroxyprostaglandin derivatives, see for example J. E.Pike, et al., J. Org. Chem., 34, 3552 (1969 indicate that the C-2hydroxy group and the C-1 acid side chain of the above less polar epimerhave a cis relationship whereas the C-2- hydroxy group and the C-1 acidside chain of the above more polar epimer have a trans relationship.

In other words the date indicate that the less polar epimer is racemicmethyl trans, cis-7-[2a hydroxy-5-(3-hydroxy-4,4-dimethyll-octenyl)cyclopentyl]-5- heptenoate and the morepolar isomer is racemic methyl trans,cis-7-[ZB-hydroxy-S-(3-hydroxy-4,4-dimethyll-octeny1)cyclopentyl]-5-heptenoate.

In the same manner but replacing methyl trans, cis-7- [2-(3-hydroxy-4,4-dime thyll--octenyl )-5-oxocyclopentyl1-5-heptenoate,Isorner B, with the corresponding Isomer A, described in Example 91,Isomer A of the title compound is obtained, y 3600, 1732 1720 cm, whichin turn can be separated into its less polar and more polar epimer. Theless polar epimer is Isomer A, reacemic methyl trans,cis-7-[2a-hydroxy-5- (3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoate [nmr (CDCl;,) 8 4.2]has a Rf= 0.68 on thin layer plates ofsilica gel using ethyl acetate-benzene (2:3) as the mobile phase and themore polar epimer of Isomer A, racemic methyl trans,cis-7-[2B-hydroxy-5- 3-hydroxy-4,4-dimethyl- 1-octenyl)cyclopentyl]-5-heptanoate [nmr (CDCl;,) 5 3.7 3.9]has a Rf= 0.47 on silica gel platesusing ethyl acetate-benzene (2:3) as the mobile phase. 1

In the same manner but using the appropriate oxo compound of formula 1,other corresponding hydroxy compounds of formula 1 in which X ishydroxy, Y is hydrogen and R is lower alkyl are prepared; for example,the corresponding lower alkyl esters of the hydroxy compounds of theproducts of Table IV. I

More specifically exemplified the choice of theoxo compound of formula1, methyl trans-7-[2-( 3-hydroxy- 3-methyll-octenyl )-5-o xocyclopentyl]heptanoate, described in Example 91, in the procedure of this examplegives methyl trans-7-[2-hydr'oxy-5-( 3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-heptanoate, 8

Likewise, the choice of methyl trans, cis-7-[2-(3- hydroxy-3-methyll-octenyl)-5-oxocyclopentyl ]-5- heptenoate, gives methyl trans,cis-7-[2-hydroxy-5-(3- hydroxy-3 -methyl- 1 -octenyl )cyclopentyl]-5-heptenoate, 'y j 3600, 1735 cm, which can be separated into its lesspolarand more polar epimer. The less polar epimer, racemic methyl trans,cis-7-[2a-hydroxy-5-(3- hydroxy-3 -methyl- 1 -octenyl )cyclopentyl1-5-heptenoate [nmr (CDCI 6 4.28]has a Rf= 0.36 on silica gel thin layerplates using ethyl acetate-benzene (3:7) as the mobile phase and themore polar epimer racemic methyltrans,-cis-7-[2B-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoate[nmr (CDCl;,) 8 3.90]has a RF 0.28 on silica gel thin layer plates usingthe same mobile phase.

Likewise, the choice of methyl trans,cis-7-[2-(3-hydroxy-4-methyl-l-octenyl)--5-oxocyclopentyl]-5- heptenoate, describedin Example 91, gives methyl trans, cis-7-[ 2-hyd roxy-5-(3-hydroxy-4-methylloctenyl)cyclopentyl]-5-heptenoate, 'y 3600,

Likewise, the choice of methyl trans,cis-7-[2-(3- hydroxy-3 -methyl- 1-octenyl )-5-oxocy clopentyl ]-4- heptenoate, described in Example 91,gives methyl 35 trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-loctenyl)cyclopentyl]-4-heptenoate,y 3600,

1730 cm, which can be separated into its less polar and more polarepimer. The less polar epimer, racemic methyl trans,cis-7-[2a-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyll-4-heptenoatehas nmr (CDCl;,) 8 2.38 (411), 4.28 (1H), 5.5 (4H) and the more polarepimer racemic methyl trans, cis-7-[2B- hydroxy--(3-hydroxy-3-methyl-1.-octenyl )cyclopentyl]-4-heptenoate has nmr (CDCl 82.4 (4H), 3.98 (11-1), 5.57 (41-1).

EXAMPLE 93 trans,cis-7-[2-1-Iydroxy-5-(3-hydroxy-4,4-dimethyl-loctenyl)cyclopentyl]-5-heptenoicAcid (1), 1; m 2, n 3, X 01-1, Y H, Z CH=C1-IC1-I R and R H and R and RCH;,)

To a solution of trans, cis-7-[2-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl1-5-heptenoate (0.536 g,Isomer B less polar epimer), described in Example 92, in methanol (5 ml)is added a solution of sodium hydroxide 1.32 ml). The mixture is stirredfor 18 hr. The solvent is removed under reduced pressure and the residuetaken up in water and extracted with ether. The aqueous liquor is thenrendered acidic with HCl (10%, 1.32 ml). The precipitate is taken upwith ether. The ether extract is washed with water, dried (Na SO and thesolvent is removed to yield the title compound, Isomer B less polarepimer, nmr (CDCl,) 8 0.84 (m, 91-1), 3.80 (m, 1H), 4.23 (m, 111), 5.27(broad, 31-1), 5.5 (m, 41-1), (i.e., racemic trans,cis-7-[2a-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyll-S-heptenoic acid).

In the same manner the lsomer B-more polar epimer, lsomer A-more polarepimer and the Isomer A-less polar epimer of methyl trans,cis-7-[2-hydroxy-5-(3- hydroxy-4,4-dimethyl- 1 octenyl )cyclopentyl]-5-heptanoate, described in Example 92, are converted to the respectiveIsomer B-more polar epimer, lsomer A- more polar epimer and the IsomerA-less polar Isomer of the title compound.

In the same manner but using the appropriate ester compound of formula 1in which X is hydroxy, Y is hydrogen and R is hydrogen are prepared; forexample the corresponding hydroxy compounds of the products of Table IV.

More specifically exemplified, the choice of methyltrans-7-[2-hydroxy-5-(3-hydroxy=3-methy1-1-octenyl)-cyclopentyllheptanoate, described in Example 92, in the procedure ofthis example gives trans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]heptanoic acid, nmr(CDCla) 8 0.9 (t, 31-1), 4.0 4.3 (m, 11-1), 5.5 (m, 21-1).

Likewise, the choice of methyl trans-7-[2-hydroxy-5-(3-hydroxy-3-methyll -octenyl)cyclopentyl]heptanoate, more polar or lesspolar epimer, described in Example 94, gives the respective more polar[nmr (CDCl;;) 8 3.95] and less polar epimer [nmr (CDCl:,) 8 4.25] oftrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)-cyclopentyl]heptanoic acid. In other wordstrans-7-[2B-hydroxy-1 and trans-7-[2a-hydroxy-5-(3- hydroxy-S-methyl-l-octenyl)cyclopentyl]heptanoic acid are obtained, respectively (seeExample 92 for the significance of the nmr peaks).

Likewise, the choice of methyl trans, cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopen- 36 tyl]-5-heptenoate,described in Example 92, gives trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoic acid, mm 3610 3450, 1718 cm.

Likewise, the choice of methyl trans, cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoate, morepolar and less polar epimer, described in Example 92, gives therespective more polar [nmr (CDCl 8 3.95 (1H), 5.55 (21-1)] and lesspolar epimer [nmr (CDCl;,) 8 4.27 (1H), 5.5 (21-1)], namely trans,cis-7-[2B-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)-cyclopentyl]-5-heptenoicacid and trans, cis-7-[2a-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyll-S-heptenoic acid respectively.

Likewise, the choice of methyl trans, cis-7-[2- hydroxy-5-(3-hydroxy-4-methyl-l -octenyl )cyclopentyll-5-heptenoate, described inExample 92, gives trans, cis-7-[2-hydroxy-5-(3-hydroxy-4-methyl-1-octenyl)cyclopentyl]-5-heptenoic acid.

Likewise, the choice of the less and more polar epimer of methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-4-heptenoate, described in Example 92,gives the respective less and more polar epimer of trans,cis-7-[2-hydroxy-5-(3- hydroxy-3-methyll -octenyl )cyclopen tyl -4-heptenoic acid. In other words, trans, cis-7-[2a-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)-cyclopentyl]-4-heptenoic acid [nmr (CDCl:,)8 4.28] and trans, cis-7-[2B-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-4-heptenoic acid[nmr (CDCl;,) 8 3.98] are obtained, respectively.

EXAMPLE 94 Methyl trans-7-[2-hydroxy-5-(3-hydroxy-3-methyl1-octenyl)-cyclopentyl]heptanoate (1;, m 2, n 3, X 01-1, Y 11, Z (Cl-1 R and R CH Rand R H) The compound of formula 3, methyl trans-7-[2-(3-oxo-l-octenyl)-5-(trimethylsilyloxy)cyclopentyl1heptanoate [3; R and RH, n 3 and L radical B wherein Z (Cl-1 m 2, R CH, and R Si(CI-I-y,,,,,,'"'" 1737, 1678, 1625 cm, nmr (CDCl:,) 8 0.12 (91-1), 0.9(31-1), 3.68 (31-1), 4.24 (1H), 6.5 (21-1), is prepared by treating theprecusor to the aldehyde of formula L-CI-IO in which L is the radical B,2(6-carboxyhexyl)cyclopentan-l-ol-3-al, prepared as described incopending Application Ser. No. 259,896, noted above, with 1.2equivalents of both trimethylchlorosilane and hexamethyldisilazane inT1-IF at 60C for 1 hour, followed by treatment of the resulting aldehydeof formula L--Cl-IO with dimethyl 2-oxoheptylphosphonate according tothe procedure of Example 2. Alternatively, the last named compound offormula 3 is prepared by treating methyltrans7-[2-(3-oxo-loctenyl)-5-hydroxycyclopentyllheptanoate, described inU.S. Pat. No. 3,455,992, issued July 15, 1969, withtrimethylchlorosilane and hexamethyldisilazane in the same manner.

The said last named compound of formula 3 (18.76 g) in dry ether ml) iscooled to 5C and added to a solution of methyl magnesium iodide(prepared from 1.23 g of magnesium turnings and 7.63 g of methyl iodide)in ml of dry ether at 5C. After 15 min. of stirring the reaction mixtureis quenched with 10 ml of saturated ammonium chloride (10 ml) whilemaintaining the temperature at 5 to 0C. The mixture is diluted withether, washed with water, dried (Na SO formula 3 and concentrated toyield methyl trans-7-[2-(3-hydroxy-3-methyl-l-octenyl)-5-(trimethylsilyloxy)cyclopentyl1heptanoate[4; R CH R, R and R H, n 3 and L radical B wherein Z (CH m 2, R CH and RS1(CH 7m 3400, 1740, 1712, 1250, 848 cm, nmr (CDCl 8 0.1 (9H), 0.92(3H), 1.3 (s, 3H), 3.7 (s, 3H), 5.5 (m, 2H)

The latter compound (18.85 g) in THF (16.8 ml), water (47.2 ml) andacetic acid (25 ml) is stirred at room temperature for 2 hr. The mixtureis cooled in an ice bath and rendered neutral by the careful addition ofsodium carbonate (20 g). The mixture is extracted with ether. The etherextract is washed with water, dried (Na SO and concentrated to yield thetitle compound, 'y 3410, 1730 cm, identical to the product of the samename described in Example 92. This product is a mixture of epimers withrespect to the asymmetric carbon of the cyclopentane ring to which thehydroxy group is attached. In the same manner as for the the titlecompound of Example 92, the present product is separated into a firstepimer (less polar) .and second epimer (more polar):

Less polar epimer: S 3430, 1730 cm, nmr (CDCl;,) 8 0.90 (t, 3H), 3.68(s, 3H), 4.2 (m, 1H), 5.55

More polar epimer: 3350, 1730 cm, nmr (CDCl 8 0.88 (t, 3H), 3.68 (s,3H), 3.90 (m, 1H), 5.55 (m, 2H).

As discussed, in Example 92, comparative data with the spectra of knownhydroxyprostaglandin derivatives indicate that the preceding less polarepimer is a racemic mixture of methyl trans-7-[2a-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]heptanoate and that the precedingmore polar isomer is racemic mixture of methyltrans-7-[28-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl1heptanoate. The respective Rfs of thesetwo racemic mixtures are 0.44 and 0.29 on thin layer plates of silicagel when using ethyl acetate-benzene (1:4) as the mobile phase.

In the same mann er but replacing methyl magnesium iodide with anequivalent a mount of ethyl magnesium bromide or propyl magnesiumbromide, methyl trans- 7-[2-(3hydroxy-3-propylf1-octenyl)-5-hydroxycyclopentyl1-5-heptenoate andmethyl trans-7-[2-(3-hydroxy-3-propyl-1-octenyl)-5-hydroxycyclopentyl]-5- heptenoate areobtained, respectively.

In the same manner but replacing the compound of methyltrans-7-[2-(3-oxo-l-octenyl)-5-(trimethylsilyloxy)cyclopentyl]--heptenoate, with the appropriatecompound of formula 3 in which L is radical B, then other compound offormula 1 in which m, n, Z, R R and R are as defined in the firstinstance X is hydroxy, Y is hydrogen and R is lower alkyl are obtained;for example, the products of formula 1 in which R is methyl described inExample 92. More specifically exemplified, replacement of the compoundof formula 3 with methyl trans, cis-7-[2-(3-oxo-1-octenyl)-5-](tetrahydropyran-Z-yl)oxy]cyclopentyl]-5-heptenoate gives methyltrans,cis-7-[2-hydroxy-5-(3-hydroxy- 3-methyl-1-octenyl)cyclopentyl]-5-heptenoate, described in Example 92.

EXAMPLE Methyltrans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]heptanoate(l; m 2, n 3, X and Y =0, Z (CH R and R CH and R and R H) To a solutionof dry pyridine (5.85 ml) in methylene chloride ml, purified by shakingwith H SO and dried over CaO, and distilled) is added chromic acid (4 g)at 15C. The mixture is stirred for 20 min. To this mixture is added asolution of the compound of formula 1 in which R is methyl, methyltrans-7-[2-hydroxy-5-hydroxy-(3-methyl-1-octenyl)cyclopentyllheptanoate, described in Example92, in methylene chloride (50 ml). The mixture is stirred for 1 hour.The reaction mixture is filtered and collected slurry on the filter padis washed with more methylene chloride. The organic phase of thefiltrate and washing are combined and washed with water, dried (Na SOand the solvent concentrated, to yield the crude product. Chromatographyof the product on a silica gel column affords the title compound,identical to the product of the same name described in Example 91.

In the same manner other compounds of formula 1 in which X is hydroxy, Yis hydrogen and R is lower alkyl, for example the other compounds offormula 1 in which R is methyl of Example 92, are oxidized to theircorresponding compounds of formula 1 in which R is lower alkyl, forexample methyl.

EXAMPLE 96 Methyl trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-1-octenyl)5-oxocyclopentyl]-5-heptenoate (l; m 2, n 3, X and Y 0, Z (Cl-1 R and RCH, and R and R H).

A mixture of the compound of formula 3 in which L is the radical C,methyl trans-7-[2-(4,4-dimethyl-3- oxo- 1-octenyl)-5-oxocyclopentyl]-5heptenoate (2.5 g, 'y 1730 1725, 1667, 1620cm ethylene glycol (360 mg) and p-toluenesulfonic acid (35 mg) in 50 mlof benzene is heated at reflux for 2.5 hr. Thereafter the mixture isextracted with ether. The ether extract is washed with water, dried(MgSO and concentrated under reduced pressure. The residue containingmethyl trans, cis-7-[2-(ethylenedioxy)-5-(4,4-dimethyl-3-oxo-1-octenyl)cyclopentyl]-5-heptenoate, 'y mm 1730, 1667, 1620 cm, is takenup in 20 ml of methanol and treated with sodium borohydride (350 mg) insmall portions with st'irringwhichis continued for 30 minutes. Thesolvent is evaporatediunder reduced pres- .sure, the residue taken up inether, washed to neutrality with water, dried (MgSO and the solventconcentrated under reduced pressure. The residue is chromatographed onsilica gel g). Elution with ethyl acetate-benzene (4:1) andconcentration of the eluant affords methyl trans,cis-7-[2-(ethylenedioxy)-5-(3-hydroxy4,4-dimethyl-l-octe:nyl)cyclopentyl]-5-heptenoate, 'y mm 3460,1740, 950 cm The latter compound (50 mg) is dissolved in methanol water(911) containing 20 mg of p-toluenesulfonic acid. This mixture isallowed to stand at room temperature overnight. The mixture isdilutedwith ether and washed with water. The ether extract is dried (MgSO andthe solvent evaporated under reduced pressure to yield the titlecompound, identical to the product of the same name described in Example91.

1. A COMPOUND OF THE FORMULA 6
 2. Dimethyl cis,trans-3-(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, as claimed in claim
 1. 3. Diethylcis,trans-3-(6-carboethoxy-2-hexenyl)4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, as claimed in claim
 1. 4. Diethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-)3-((tetrahydropyran-2-yl)oxy)-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, as claimed in claim 1.5. Diethyltrans-3-(6-carboethoxyhexanyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, as claimed in claim
 1. 6. Diethyltrans-3-(6-carboethoxyhexanyl-4-(3-((tetrahydropyran-2-yl)oxy)-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, as claimed in claim
 1. 7.Diethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-4-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,as claimed in claim
 1. 8. Diethyl cis,trans-3-(6-carboethoxy-3-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,as claimed in claim
 1. 9. The compound of claim 1 wherein R7 is hydrogenor a protecting group selected from the group consisting oftetrahydropyran-2-yl, trimethylsilyl, dimethylisopropylsilyl, andtert-butyl.